Optically active 3-hydroxy-N-benzylpyrrolidine and its derivatives are widely used as intermediates of various chiral medicines such as carbapenem antibiotics (panipenem), vasodilation (Barnidipine) or antihypertensive (Darifenacine, Lirequill, Clina floxacine) drugs (EP 483580; EP 330469; EP 304087; U.S. Pat. No. 5,463,064; U.S. Pat. No. 5,281,711; U.S. Pat. No. 5,109,008; U.S. Pat. No. 4,916,141; WO 91/09013). Several compounds are also reported to be clinically tested. Enantiomerically pure 3-hydroxy-N-benzylpyrrolidine is also a useful intermediate for various agrochemicals. Literature methods for preparing enantiomerically pure 3-hydroxy pyrrolidine and its derivatives are as follows.
1) A process for the preparation of 3-hydroxypyrrolidine involves decarboxylation of chiral 4-hydroxy-2-pyrrolidinecarboxylic acid (WO 91/09013; U.S. 5233053, Chem. Lett. 1986, 893). This process suffers from low yield and a number of synthetic steps.
2) Hydroboration of N-substituted 3-pyrrolidine with diisopinocomphenyl borane followed by oxidation with alkaline hydrogen peroxide gave enantiomerically pure 3-hydroxypyrrolidine (Brown H. C., et. al J. Am. Chem. Soc., 1986, 108-2049; Brown, H. C., et al, J. Org. Chem.; 1986, 51, 4296). The process may not be suitable for industrial production because of the use of special borane reagent.
3) One of the common methods for the preparation of N-substituted 3-hydroxy pyrrolidine is the condensation reaction of natural malic acid with benzylamine and subsequent reduction reaction with a strong reducing agent (Synth. Commun. 1983, 13, 117 and Synth. Commun. 1985, 15, 587). Optically active N-benzyl-3-hydroxy pyrrolidine was also prepared starting from glutamic acid. The intermediate 3-hydroxypyrrolidinone is reduced by a strong reducing agent to give N-benzyl-3-hydroxypyrrolidine (Synth. Commun. 1986, 16, 1815). Although the above methods have the advantages that chiral 3-hydroxypyrrolidine and its derivatives can be produced from commercially available raw materials, however, the reducing agent used in these processes are expensive and the required reaction conditions are not suitable for large scale production.
4) 3-Hydroxy pyrrolidine was also reportedly prepared by reacting 1, 4-dibromo-2-butanol with benzyl amine (J. Med. Pharm. Chem., 1959, 1, 76). Selective bromination at 1, 4 position is not controlled easily, and the yields are low (31%). Moreover, the use of expensive brominating reagents makes the process unsuitable for large scale production.
5) Some classical processes used chemical resolution agents, to obtain optically active 3-hydroxypyrrolidine and its derivatives from racemic mixtures [(JP 05/279326 (1993); JP 05/279325 (1993); JP 04/164066 (1992)]. Again the reported yields are low, and these processes are not efficient for large scale production.
6) Process for resolving racemic 3-hydroxypyrrolidine derivatives using enzymatic resolution via hydrolysis [(WO 95/03421 (1995); U.S. 5187094 (1993); JP 01/141600 (1995)] and esterification [(WO 95/03219 (1995); JP 05/227991 (1993); JP 04/131093 (1992)] lack practicality and the synthesis of racemic starting material is also a drawback.
7) Use of biocatalyst for the preparation of optically active 3-hydroxypyrrolidine, where in an oxygen atom is inserted stereoselectively in the corresponding pyrrolidine nucleus is one of the promising processes, however, low yield, high dilution and low enantiomeric excess of the product are some of the main draw backs (U.S. Pat. No. 7,141,412). Enzymatic hydroxylation of pyrrolidines is complicated. Hydroxylation of N-benzyl-3-hydroxypyrrolidine with Pseudomonas putida gave corresponding 3-hydroxypyrrolidine in low yield as well as low enantiomeric excess (EP 1002871). There is also a report of hydroxylation by Khim. Geterotsikl. Soedin. using specific fungi, Cunninghamella verticillate, or Aspergillus niger (Chemical Abstract, 1993, 118: 6835C). It is doubtful whether the method is applicable to the hydroxylation of N-acylpyrrolidines, moreover the process suffers from low yield. The biocatalytic hydroxylation process is perhaps the only process which is being commercially used for the production of the target molecules.
8) Process for preparing enantiomerically pure 3-hydroxypyrrolidinone [(JP 06/141876 (1994); WO 98/23768 (1998)] also faces the same difficulties as mentioned above.
9) Recently 3-hydroxypyrrolidine and its N-substituted derivative were prepared by cyclisation of 4-halo-3-hydroxy butane derivatives [(EP 452143 (1991)] e.g. cyclization of enantiomerically pure 4-chloro-3-hydroxy butylnitrile [(EP 431521 (1988)], and 3-chloro-2-hydroxy propionitrile (WO 2007/024113). However, enantiomerically pure starting materials are expensive and not easily available, so the process is not less viable. It is evident that though, there are various methods for the preparation of enantiomerically rich N-benzyl-3-hydroxypyrrolidine and its derivatives documented in the literature, yet an efficient process of preparation of enantiomerically pure product from an inexpensive and easily available raw material is one of the important challenges in the field of synthetic and medicinal industry.
The present process of the preparation of both the enantiomers i.e. (R) and (S)-3-N-benzyl-3-hydroxypyrrolidines with high optical purity from the easily available raw material with its sustainable supply, renewable source, facile reaction methodology and high yields, makes it an attractive and commercially viable method.